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CASE BASED REVIEW
Ahead of print publication  

Deficiency of adenosine deaminase 2 in an elderly female with multiple intestinal ulcers and hemorrhagic stroke


1 Department of Nephrology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Rheumatology, Command Hospital Air Force, Bengaluru, Karnataka, India
3 Department of Internal Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India

Date of Submission27-Dec-2020
Date of Acceptance02-Sep-2021

Correspondence Address:
Vijoy Kumar Jha,
Department of Nephrology, Command Hospital Air Force, Post- Agram, Old Airport Road, Bengaluru - 560 007, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_356_20

  Abstract 


Deficiency of adenosine deaminase 2 (DADA2) is a recently identified monogenic systemic inflammatory vasculopathy with variable clinical phenotype. The majority of reported patients are in pediatric age group. In this case report, we present a case of DADA2 in an elderly female, who presented initially with multiple episodes of loose motions with bleeding per rectum and was diagnosed endoscopically as multiple rectal hemorrhagic ulcers. During her hospital stay, she had generalized tonic-clonic seizures and was detected to have a hemorrhagic stroke. The patient was managed with steroids, cyclophosphamide, and other supportive measures. She had excellent recovery with the disease in remission on low-dose steroids and mycophenolate mofetil.

Keywords: Deficiency of adenosine deaminase 2, hemorrhagic stroke, hemorrhagic ulcer, neutropenia



How to cite this URL:
Jha VK, Kumar M H, Balakrishnan A, Mahapatra D. Deficiency of adenosine deaminase 2 in an elderly female with multiple intestinal ulcers and hemorrhagic stroke. Indian J Rheumatol [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=328981




  Introduction Top


Deficiency of adenosine deaminase 2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. Highly variable clinical presentation makes the early diagnosis very difficult. Twenty-four percent of reported patients present before 1 year of age and 77% present before the age 10 years.[1] The oldest patient described in literature presented at age 59 years with leg ulceration.[2] Gastrointestinal involvement includes diffuse abdominal pain and inflammatory bowel disease in up to 10% of patients with intestinal necrosis, bowel perforation, stenosis, or aneurysm of the mesenteric artery/celiac artery.[1] Here, we present a case of DADA2 in an elderly female who presented with complications of multiple rectal hemorrhagic ulcers followed by esophageal vasculitis and hemorrhagic stroke.


  Case Report Top


A 66-year-old postmenopausal woman was admitted with a history of low-grade fever, easy fatiguability, diffuse pain abdomen, loose stools, and bleeding per rectum of 2-week duration. Pain abdomen was continuous, colicky in nature, and aggravated by food intake. Loose stools were of large bowel type, 10–12 episodes/day, and mixed with fresh blood. There was no history of dysphagia, heartburns, melena/hematemesis, jaundice, and abdominal distension. Past history was insignificant without any episodes suggestive of connective tissue disorders. Clinically she was poorly built and malnourished woman with body mass index of 16.8 kg/m2. She was mildly dehydrated and sick looking. She was initially managed as a case of acute gastroenteritis, but as the symptoms of large bowel diarrhea with blood per in stool persisted, she underwent colonoscopy. Colonoscopy revealed patchy ulcers with hyperemia in the rectum and sigmoid colon. Her hematological and biochemical investigations including kidney function/liver function test were within the normal range on admission. She continued to have abdominal pain even with adequate fluid resuscitation and IV antibiotics. After day 5, she started deteriorating with persistent abdominal pain, drowsiness, and severe generalized weakness. Investigations revealed neutrophilic leukocytosis (total leukocyte count – 20,900–17,800/mm3and neutrophil 88%–91%) and deranged liver function test (serum bilirubin – 3.7–4.2 mg/dl, direct bilirubin – 0.47–0.36 mg/dl, serum albumin – 2.37–1.38 g/dl, and aspartate transaminase/alanine aminotransferase-24–48 IU/L/12–14 IU/L). Her urine output and kidney function test were normal. On day 7 of admission, she was planned for contrast-enhanced computed tomography (CECT) abdomen in view of persistent diffuse abdominal pain. While being shifted for the same, she developed generalized tonic-clonic seizure and worsening of sensorium. Her blood pressure remained in higher range, requiring two drugs antihypertensives. In view of poor responsiveness and seizure, she was intubated and put on invasive ventilation. She underwent noncontrast computed tomography (CT) of the head which revealed foci of cortical hemorrhages measuring 15 mm × 13 mm anteroposterior (AP) × transverse (TR) in the left basifrontal region with surrounding edema. Focus of cortical hemorrhage measuring 14 mm × 15 mm (AP × TR) was also noted in the lateral aspect of right temporal lobe with the presence of subarachnoid hemorrhage in these regions. CT angiogram revealed a bilateral basilar artery aneurysm [Figure 1]. CECT of the abdomen with angiographic images was suggestive of significant stenosis of the celiac trunk at its origin and multiple microaneurysm involving multiple segmental renal arteries of both kidneys [Figure 2]. Urine routine examination/microscopy revealed protein 2 + with 2–3 red blood cells/high-power field. On day 10, she was noticed to have coffee ground collection – 500 ml through Ryle's tube. She was also noted to have melena. Bedside upper gastrointestinal (GI) endoscopy and colonoscopy were planned. In upper GI endoscopy, multiple irregular esophageal ulcers at the gastroesophageal junction were viewed, and on repeat colonoscopy, multiple ulcers from the rectum up to cecum suggestive of ischemic ulcers were visualized and hemostasis was achieved [Figure 3] and [Figure 4]. Ileocecal junction was free. Intestinal biopsy was not done, as there was a risk of bleeding in view of hemorrhagic ulcers. Her autoimmune markers (antinuclear and antineutrophil cytoplasmic antibodies [ANCAs]) were negative. Antinuclear antibody test was done by both indirect fluorescent antibody and enzyme immunoassay. ANCA was done with indirect immunofluorescence tests. Tumor markers (CA-125, carcinoembryonic antigen, and CA 19.9) were normal. Other investigations were erythrocyte sedimentation rate – 25–52 mm fall, C-reactive protein-200 ng/ml, angiotensin-converting enzyme – 15 IU/L (15–82), antiphospholipid antibody workup (anticardiolipin antibodies immunoglobulin G (IgG)/immunoglobulin M (IgM) by enzyme-linked immunosorbent assay (ELISA), anti-beta-2 glycoprotein 1 antibody IgG or IgM by ELISA, and lupus anticoagulants by functional assay) – negative, viral markers (HIV, HBsAg, and anti-HCV) – negative, 2-D echo – normal, and serum protein electrophoresis – normal. Absolute CD4 count and CD8 count were 77 cells/cmm (447–1846) and 20 cells/cmm (209–924), respectively. In view of multisystem involvement in the form of vasculitic ulcers, hemorrhagic stroke, and ecstatic arteries, she was managed as a case of atypical polyarteritis nodosa (PAN) versus DADA 2. The neurological manifestation is unusual in classic PAN, and hence, a clinical diagnosis of DADA2 deficiency was considered. Plasma ADA2 activity was deficient in her (0.01 IU/L, reference range-6.9–59.7 IU/L). She was started on pulse steroids (500-mg IV methylprednisolone for 5 days) and immunosuppressants–cyclophosphamide (500-mg IV with premedications) under potent antibiotics coverage. On day 6th postimmunosuppression, she was noted to have drop-in leukocyte count with a predominant fall in neutrophils. She had a fever with chest X-ray showing nonhomogeneous opacity in the right lower zone. She was managed as febrile neutropenia. Antifungal and antiviral were also added. She had gradual improvement in her symptoms. Her sensorium gradually improved and she was weaned off ventilation. She was put on low-dose steroid (20 mg/day) thereafter and mycophenolate mofetil was added once leukocyte count improved. Repeat colonoscopy after 3 months revealed healed ulceration and she had no bleeding per rectum. Clinical exome reported after 1 ½ months revealed CECR1 gene transcript at exon 9 with variant c. 1334T>c (p. Met445Thr) heterozygous with autosomal recessive inheritance.
Figure 1: Noncontrast computed tomography head and computed tomography angiogram – foci of cortical hemorrhages measuring 15 mm × 13 mm anterosuperior x transverse (marked as arrow) noted in left basifrontal region with surrounding edema. Focus of cortical hemorrhage measuring 14 mm × 15 mm (AP × TR) was also noted in the lateral aspect of right temporal lobe with the presence of subarachnoid hemorrhage in these regions. Computed tomography angiogram is suggestive of bilateral basilar artery aneurysm (marked as pointed arrow)

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Figure 2: Contrast-enhanced computed tomography of the abdomen with angiographic images suggestive of significant stenosis of the celiac trunk at its origin and multiple microaneurysm involving multiple segmental renal arteries of both kidneys (marked as arrows)

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Figure 3: Upper gastrointestinal endoscopy showing multiple irregular esophageal ulcers at the gastroesophageal junction

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Figure 4: Colonoscopy showing multiple ulcers from the rectum up to cecum suggestive of ischemic ulcers

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  Discussion Top


DADA 2 is an autosomal recessive disease resulting from loss-of-function mutations in ADA2, formerly named CECR1 (cat eye syndrome chromosome region, candidate1) gene. These patients had a large phenotypic variability that cannot be fully explained by the impact of causal mutations on protein function and a degree of residual enzymatic activity. A role for genetic, epigenetic modifiers, and environmental factors has also been proposed in the clinical expression of the disease.[3] Our patient had no comorbidities at this age and was admitted for the first time in hospital with a history of bloody diarrhea followed by generalized weakness. Parents of DADA2 patients are typically asymptomatic, as for protein functions, only 50% of normal enzymatic activity is sufficient. It has also been suggested that patients with undetectable ADA2 activity tend to have a more severe phenotype.[3] The ADA2 activity in this case was undetectable and she had progressive worsening of her clinical conditions and multisystem involvement. The ADA2 mutation, in our case, was heterozygous and whether this heterozygosity predispose to late-onset stroke, polygenic vasculitis, and other cardiovascular disease remains to be studied.

ADA2 deficiency is associated with monocyte-macrophage polarization toward the M1 subset which is known to promote inflammation and tissue damage.[4] ADA2 is also very critical for the maintenance of vascular integrity. In a vitro three-dimensional model, it has been seen that ADA2 in M2-like glioma-associated macrophages mediate cross-talk between macrophages and pericytes through a platelet-derived growth factor-dependent pathway which results in neo-angiogenesis.[5] ADA2 deficiency in the present case predisposed the patient to multiple vasculitic ulcers with hemorrhages due to the involvement of small vessels. Small- and medium-sized arteries vasculopathy is the major clinical feature of DADA2. Although skin and central nervous system are the most commonly involved system, other tissues such as the renal, liver, coronary, and GI are also affected to various degrees.[1] In our case, involvement of bilateral basilar artery, ectatic celiac artery, and microaneurysm of bilateral segmental renal arteries is also suggestive of vasculopathy of small- and medium-sized arteries. The diagnosis of DADA2 requires a high index of suspicion when evaluating patients with PAN whose disease course is unusual and those which are not associated with hepatitis B virus infection. The present case had clinical features resembling PAN with hypertension, GI, renal, and multisystem involvement. The dominant central nervous system (CNS) manifestation in our patient goes in favor of DADA2.

It has been seen that of all the reported patients, 50% have experienced one or more neurological issues. Typical neuroimaging consists of acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter. Hemorrhagic stroke and intracranial bleeding seem to be part of the clinical spectrum in 12% of cases.[6],[7] In the index patient, the individual was conscious and well oriented on admission, but she deteriorated thereafter with progressive drowsiness which initially was attributable to generalized weakness. The neuroimaging in this case was done as the patient had repeated episodes of generalized tonic-clonic seizure which was suggestive of hemorrhagic stroke. In DADA2 patients, unlike in standard care for stroke patients, it is recommended to discontinue treatment with aspirin and other anticoagulants as hemorrhagic stroke is a potential complication.

The standard treatment is steroids and tumor necrosis factor (TNF)-inhibition, which is successful in suppressing inflammation and in prevention of vascular events. Other drugs such as azathioprine, cyclosporine, tacrolimus, cyclophosphamide, and methotrexate have all been used yet with little benefit.[6] Future therapies may include recombinant ADA2 protein or gene. Hematopoietic stem-cell transplantation may be considered in those patients presenting with hematological disease and immunodeficiency not responding to TNF-inhibitors. It has been reported to control both the immunological, the hematological, and the vascular phenotype of DADA2. However, in our case, we managed the case with pulse steroid and cyclophosphamide with excellent outcomes. We got DADA2 Clinical Exome report after 45 days. The patient was treated on an urgent basis with cyclophosphamide due to organ-threatening damage by medium vessel vasculitis. In our case, we used mycophenolate mofetil alone after stopping cyclophosphamide. Mycophenolate mofetil was added after the cyclophosphamide pulse once total leukocyte counts became normal. Cyclophosphamide was given initially only at a dose of 500 mg (as per her body surface area/glomerular filtration rate). Low CD4 and CD8 in this case probably were part of the generalized lymphopenia which the patient manifested at presentation.

The index patient was unique and different from other patients earlier reported in the literature. First, DADA2 manifestation at the age of 66 years has not been reported. Second, the acute presentation of multifocal medium vessel vasculitis in an adult in the form of involvement of GI tract and CNS along with constitutional symptoms is not reported in the literature. In the absence of any biopsy, the esophageal ulcers were ascribed to vasculitis as stress-related esophageal ulcers are uncommon to rare and without any ulcers in the stomach and duodenum. These ulcers were numerous and irregular too.

The variants of the CECR1 gene alleles identified in our patient were also new ones. The patient was given steroid and cyclophosphamide pulse and had got dramatic improvement initially and complicated later on with febrile neutropenia and pneumonia. We did not administer TNF inhibitor in this patient and had got excellent results. This case also highlights the expanding spectrum of genetic mutations causing DADA2, which might present with unknown diverse presentations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 2018;38:569-78.  Back to cited text no. 1
    
2.
Lamprecht P, Humrich JY, Diebold I, Riemekasten G. Diagnosis of deficiency of adenosine deaminase 2 with early onset polyarteritis nodosa in an adult patient with a novel compound heterozygous CECR1 mutation. Clin Exp Rheumatol 2018;36 Suppl 111:177.  Back to cited text no. 2
    
3.
Van Montfrans JM, Hartman EA, Braun KP, Hennekam EA, Hak EA, Nederkoorn PJ, et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford) 2016;55:902-10.  Back to cited text no. 3
    
4.
Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, et al. Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci 2017;74:555-70.  Back to cited text no. 4
    
5.
Zhu C, Chrifi I, Mustafa D, van der Weiden M, Leenen PJ, Duncker DJ, et al. CECR1-mediated cross talk between macrophages and vascular mural cells promotes neovascularization in malignant glioma. Oncogene 2017;36:5356-68.  Back to cited text no. 5
    
6.
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370:911-20.  Back to cited text no. 6
    
7.
Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014;370:921-31.  Back to cited text no. 7
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

 
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